Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

Andreas Schneeweiss, Tjoung-Won Park-Simon, Joan Albanell, Ulrik Lassen, Javier Cortés, Veronique Dieras, Marcus May, Christoph Schindler, Frederik Marmé, Juan Miguel Cejalvo, Maria Martinez-Garcia, Iria Gonzalez, Jose Lopez-Martin, Anja Welt, Christelle Levy, Florence Joly, Francesca Michielin, Wolfgang Jacob, Céline Adessi, Annie Moisan, Georgina Meneses-Lorente, Tomas Racek, Ian James, Maurizio Ceppi, Max Hasmann, Martin Weisser, Andrés Cervantes, Andreas Schneeweiss, Tjoung-Won Park-Simon, Joan Albanell, Ulrik Lassen, Javier Cortés, Veronique Dieras, Marcus May, Christoph Schindler, Frederik Marmé, Juan Miguel Cejalvo, Maria Martinez-Garcia, Iria Gonzalez, Jose Lopez-Martin, Anja Welt, Christelle Levy, Florence Joly, Francesca Michielin, Wolfgang Jacob, Céline Adessi, Annie Moisan, Georgina Meneses-Lorente, Tomas Racek, Ian James, Maurizio Ceppi, Max Hasmann, Martin Weisser, Andrés Cervantes

Abstract

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development.

Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

Keywords: Biomarker; ErbB3; Heregulin (HRG); Human epidermal growth factor receptor 2 (HER2); Human epidermal growth factor receptor 3 (HER3); Metastatic breast cancer; Pertuzumab; Phase I.

Conflict of interest statement

Conflicts of interest

Andreas Schneeweiss, Tjoung-Won Park-Simon, Ulrik Lassen, Marcus May, Christoph Schindler, Frederik Marmé, Juan Miguel Cejalvo, Maria Martinez-Garcia, Iria Gonzalez, Christelle Levy, Florence Joly, Andrés Cervantes declare no conflict of interest, Joan Albanell, Roche advisory board participation; Javier Cortés, Remuneration from Roche, Eisai, Novartis, Celgene, Pfizer; consultant or advisory board participation for Roche, Celgene, AztraZeneca and Cellestia, Biothera, Merus; Veronique Dieras, Remuneration from Roche, Pfizer, Novartis, Lilly, AstraZeneca; consultant or advisory board for Mylan, Puma; Jose Lopez-Martin, Consultant or advisory board for Roche, AstraZeneca, Celgene, Pfizer, BMS, MSD, Novartis, Pierre Fabre; stock ownership of PharmaMar; Anja Welt, Remuneration from Roche, Novartis, Pfizer, AstraZeneca, Interplan; Consultant or advisory board from Pfizer, Roche, Novartis, Tesaro; Funding from Novartis; Francesca Michielin, Celine Adessi, Sponsor employees; Wolfgang Jacob, Annie Moisan, Georgina Meneses-Lorente, Tomas Racek, Maurizio Ceppi, Max Hasmann, Martin Weisser, Sponsor employees and sponsor stock ownership; Ian James, Sponsor consultant from A4P.

Ethics approval and consent to participate

Local ethics committee approval was obtained and all patients provided written informed consent. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki in nine centers in Denmark, France, Germany and Spain. The following ethics committees approved the study: Denmark (Videnskabsetiske Komiteer Region Hovedstaden on 24 Apr 2013), Spain (Hospital Clinico Universitario de Valencia CEIC on 07 May 2013; CEIC Hospital Universitario 12 de Octubre on 07 May 2013; CEIC Parc de Salut Mar; IMIM- Hospital del Mar, C/ Dr. Aiguader, 88, Planta 1, 08003, Barcelona on 07 May 2013; CEIC Hospital Vall D’Hebron on 15 Oct 2014), Germany (Ethikkommission der Medizinischen Fakultät Heidelberg on 21 Aug 2013 and on 23 Feb 2015) and France (Comite de protection des personnes Ile de France III on 17 Jun 2013 and on 30 Jun 2013).

Figures

Fig. 1
Fig. 1
Best percent change from baseline in sum of target lesions and best confirmed response according to RECIST. a Cohort 2 patients and b first-line patients of Cohort 2 (left) and patients of Cohort 3 (right). a Unconfirmed partial response. Two patients are not shown who were discontinued prior to the first on-treatment tumor assessment

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